And over the summer, it began to look as though the monster would prevail.

After six months of treatment and a grueling eight rounds of chemotherapy, Matthews’s lymphoma had stopped responding to medicine’s best efforts. For most patients, that’s the end of the line. Matthews’s doctors, however, gave him one more option.

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It would involve siphoning out his white blood cells and sending them on a cross-country expedition so genetic engineers in a factory outside Los Angeles could train them in the ways of cancer killing. The cells would be rewired and nurtured in an incubator, then frozen and shipped to Boston to be dripped back into his veins.

The experimental process would take a month and would require the combined efforts of more than 150 doctors, nurses, scientists, and couriers. Their work on Matthews and other patients would eventually validate the paradigm-shifting gene therapy, known as CAR-T. The successful clinical trials would lead to regulatory approval of two CAR-T treatments for rare and deadly blood cancers.

But Matthews didn’t know all that when he agreed to send his cells on a last-chance odyssey.

All he knew was that the monster was winning.

His cancer, an aggressive subtype called diffuse large B-cell lymphoma, or DLBCL, was what doctors call refractory. “We thought chemo and cancer was bad,” said Matthews, who runs a small business that supplies fire departments, “but when you hear the word ‘refractory,’ you pretty much know what that means.”

“We thought chemo and cancer was bad. But when you hear the word ‘refractory,’ you pretty much know what that means.”

Dave Matthews, cancer patient

Only about 8 percent of patients with refractory DLBCL respond to yet more chemo. The rest are sent home with instructions on how to manage pain in their waning days. At the median, patients survive for about seven months.

At 51, Matthews is fit, active, and unfailingly positive. Yet his doctors explained that his immune cells no longer knew how to fight. They had become tolerant to his lymphoma, allowing cancer cells to flourish unchecked.

A clinical trial offered some hope that that the cells could be retrained — could get back their fighting spirit, the medical team at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital told Matthews. In an earlier clinical trial of the CAR-T treatment, roughly one-third of patients with the same stubborn disease saw their cancer disappear after three months, while more than three quarters had at least a partial response to therapy.

There were risks. A handful of patients had died in previous studies, overcome by a rapturous fever or killed by the treatment’s toxic effects on the brain. And the therapy itself leaned toward science fiction. The long-term effects are not yet known.

It was all detailed in a weighty ream of data that Matthews and his wife, Diane, pored over in their home in a Connecticut town about 90 minutes south of Boston.

“Why wait?” had become something of a mantra for the couple. Together for three years, they’d considered putting off a wedding until all of their six children — three apiece from previous marriages — had finished school. Then Matthews was diagnosed. “Why wait?” they thought, and had married in June, six months after he found he had cancer.

Now, mindful of that word “refractory” and all its implications, “Why wait?” seemed just as relevant to the trial.

A small bag of worn-out T cells

Dave Matthews’s CAR-T journey started in late August, in a small room at the Brigham’s blood donor center.

Doctors stuck him with a pair of IVs, one in each arm, with what’s called an apheresis machine in the middle. Over the next five hours, his entire blood supply passed twice through the machine, which filtered out T cells, a type of white blood cells.

The result: a bag the size of a packet of M&Ms, packed with Matthews’s T cells. That bag was sent immediately to a lab at Dana-Farber, where a team led by cell transplant expert Dr. Sarah Nikiforow repeatedly tested the cells to ensure their purity. Then they went back in the bag and straight into a nanocooler, where they were kept at a temperature just above freezing.

That’s when the couriers arrived. The cooler was loaded onto a plane and sent to Kite Pharma, a T cell training center in El Segundo, Calif., lined with stainless steel tanks.

Kite was ready. The day Matthews joined the CAR-T trial, the company had assigned him a one-of-a-kind ID number so they could track his T cells on their flight west. Once the bag arrived in the nanocooler, it was tagged with a bar code representing that ID.

It’s a deeply important and practical measure, as a mix-up could lead to a patient receiving someone else’s cells, with disastrous results.

But it also has a humanizing effect on the manufacturing process, as every Kite employee knows they are working on a bespoke treatment for a particular patient.

“You know their life is in your hands,” said Tim Moore, Kite’s executive vice president of technical operations. “I can honestly say people really get that and are highly motivated to make a difference for that patient.”

“You know their life is in your hands.”

Tim Moore, executive vice president at Kite

Once Matthews’s cells arrived at Kite’s facility, workers tested them to ensure they had not been thawed or frozen too deeply en route. They then purified the contents of the bag, isolating the T cells from any stray plasma or red blood cells that may have snuck in back in Boston. From there, the cells went into an incubator to grow.

Then the genetic engineering began.

A dose of CAR-T therapy is frozen and prepared for shipping so it can be infused into the patient.Kite/Gilead

Growing an army of killer cells

In a process called transduction, Kite used a harmless virus to inject a gene into Matthews’s T cells. The gene wires the cells to seek out a protein called CD19, which is present on the surface of lymphoma cells.

The goal: teach the T cells, which had been so complacent earlier in the summer, to swarm Matthews’s cancer cells — and kill them.

But a few killer cells couldn’t tame the monster alone. Matthews would need an army of them.

So Kite’s team put the edited cells into an incubator and left them alone to replicate for a week, until there were 2 million of them. That’s what it takes to make an effective dose of CAR-T.

Another week passed: Kite repeatedly tested the cells to make sure the treatment was sterile, potent, and ready to ship.

Only then did the couriers return to send the CAR-T army back to Boston.

Matthews, for his part, passed the time at home, trying to go about life as normally as possible while scientists “did their magic” with his T cells.

“In a way it’s kind of comforting” knowing a multibillion-dollar pharmaceutical company is working to cure your personal cancer, he said. “But maybe a little nerve-wracking, too.”

About two weeks after apheresis, he got a call: His T cells were ready for battle and en route back to the hospital. On Sept. 18, he would get them back. But first, he’d have to prepare.

Priming the body for an invasion

Before defrosting Matthews’s CAR-T dose, doctors administered three consecutive days of chemo. This time, the target wasn’t his cancer; they were trying to kill off his remaining T cells. The process, often referred to as priming, is meant to clear the way for the CAR-Ts and allow them to flow freely in the patient’s blood to maximize their cancer killing effect.

The following Monday, Matthews checked back into the hospital. And the next day, in a 15-minute procedure he called “uneventful,” he was reunited with his well-traveled T cells.

Then he waited.

The first day was no sweat, Matthews said, beyond a bit of fatigue. On day three, with Diane at his side, he clocked four miles wending through the hospital hallways.

The most common reaction to CAR-T therapy is called cytokine release syndrome, which results from the immune system kicking into overdrive. In a way, it’s more a feature than a bug, as feverish symptoms mean CAR-T is doing its job.

But it can be severe and even deadly, said Nikiforow, the Dana-Farber oncologist, with roughly one-third of CAR-T patients ending up in intensive care as a result.

Matthews’s fever put a stop to all the walking, but it never got too severe, and doctors eventually tamped it down with some “fancy footwork,” Nikiforow said. A few neurological side effects ensued, leaving Matthews sometimes struggling to find the right words to fit a sentence and experiencing intermittent “loopiness,” he said. And for about 24 hours, his salivary glands swelled up, distending his jawline and stoking a headache.

Each effect eventually subsided, and Matthews went home about a week later, anticipating an answer to the only question that had come to matter: Did it work?

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Last week, a month after treatment, Matthews returned to Dana-Farber with Diane at his side and learned that he recorded a partial response. That means the CAR-T therapy had reduced his tumor burden, but the cancer has not vanished.

“So he goes into that 75 percent or so who are showing a response, and we’re hoping he’s going to fall into the complete response group” in the coming months, said Nikiforow, pausing to knock three times on a wooden table.

“I look at the news that I was given today as a home run,” Matthews said.

His next scan is on the calendar for December, and he’s hopeful that, given more time to percolate in his veins, his newly trained T cells will perform even better.

But even if they don’t, Matthews is effusive about the hope CAR-T might offer to others. Since his diagnosis, he’s been an active member of online communities for lymphoma patients, passing on positive thoughts and consolation.

“At 51 years old, I have a lot of life left in me — a lot of good left to do in this world. And I’m not the only one.”

Dave Matthews

“We all know someone — family, friends, someone in our community — who has cancer,” Matthews said. “I look at my subgroup, my cancer, and I think, what if this wasn’t available to me? At 51 years old, I have a lot of life left in me — a lot of good left to do in this world. And I’m not the only one. With this therapy, hundreds, maybe thousands, of lives will be saved, and think of those people and all the good they’ll do in their lives. We can’t quantify that.”

Matthews didn’t have to pay for his CAR-T therapy; because he got it in a clinical trial, Kite — which is a division of Gilead Sciences — picked up the tab. Future patients may not be so fortunate.

The first CAR-T to win regulatory approval, from Novartis, carries a list price of $475,000 for a one-time dose. The one Matthews received goes for $373,000. And that’s just for the treatment; it doesn’t include all the hospital costs.

“We have to figure out how to make these treatments available to everyone,” Matthews said. “There’s good in all of us, and everyone should be afforded the same experience and opportunity I had.”

Cancer cells cannot exist without trans-membrane carbonic anhydrases, which regulate pH inside and around the cancer cells. For that reason inhibitors of CA9, CA12, and CA14 inhibit and prevent cancer growth. Late professor Thomas Marren, developed soluble preparation of sulfonamide/dorzolamide to treat and control glaucoma. I discovered that these inhibitors totally suppress these enzymes and inhibit cancer cell growth. Daily intake of this drug (1-2 drops in the eye or nose) is safe and would prevent/cure cancer. This is effective, not expensive and already approved by the FDA for topical application in the eye to treat and manage glaucoma.

Daily intake of this drug (1-2 drops in the eye or nose) is safe and would prevent/cure cancer.

Thank you for incredible job you did in putting together all the facts, my personal accounts/interviews conducted, in making this not only an informative but interesting read. I’ve had many friends and family members comment on how educational it was and eye opening for them.

Has fever, as a result of an infectious disease, ever been reported as stimulating T cell proliferation and causing the same cytokine storm? If so, it would be a less expensive alrernative to deliberately infuce an infection

Yes, a good insight — over 100 years ago William Coley injected patients with cancer with a broth of bacterial species, mostly Streptococcus and Serratia. The resultant “Coley’s toxin” induced cytokines that led to some remissions. Some patients died of infection. The Coley’s toxin experience is often cited by immunotherapists as helping inspire their work. The bacterial injection was certainly much cheaper but the new CAR-T cells are many times more effective and targeted more narrowly at the cancer.

CAR-T is promising in supercharging the immune system to fight off cancers. Let science also go upstream and figure out what is degrading the individual immune system in the first place, enabling the cancers to grow, spread and accelerate. There is more being done in this arena than many are aware.d